PATIENT SAFETY RECOMMENDATIONS FOR COVID-19 EPIDEMIC OUTBREAK

Lessons from the Italian Experience

Authors:

Micaela La Regina, Michela Tanzini, Francesco Venneri, Giulio Toccafondi, Vittorio Fineschi,
Peter Lachman, Luca Arnoldo, Ilaria Bacci, Alessandra De Palma, Mariarosaria Di Tommaso,
Andrea Fagiolini, Marco Feri, Raffaele La Regina, Antonino Morabito, Stefano Parmigiani,
Mario Plebani, Elisa Romano, Chiara Seghieri, Pierfrancesco Tricarico, Giorgio Tulli, Riccardo
Tartaglia.

March 25th, 2020

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INTRODUCTION........................................................................................................................ 3

The Work System

1. GENERAL RECOMMENDATIONS FOR THE WORK SYSTEM .................................................. 4

Clinical pathway

2. RECOMMENDATIONS FOR DIAGNOSIS…………………………………............................................. 8

3. RECOMMENDATIONS FOR HOSPITAL TREATMENT............................................................ 12

4. THE ETHICS OF TREATMENT DECISIONS............................................................................. 15

5. RECOMMENDATIONS FOR SURGERY.................................................................................. 16

6. RECOMMENDATIONS FOR PREGNANT WOMEN................................................................ 17

7. RECOMMENDATIONS FOR PEDIATRIC PATIENTS............................................................... 19

8. RECOMMENDATIONS FOR HOSPITAL DISCHARGE............................................................. 20

9. RECOMMENDATIONS FOR HOME ISOLATION.................................................................... 22

10. RECOMMENDATIONS FOR PERSONS ON QUARANTINE ...................................................23

11. RECOMMENDATIONS FOR ONCOLOGIC AND IMMUNOSUPPRESSED PATIENTS............. 24

12. RECOMMENDATIONS FOR MORGUE and MORTUARY OPERATING PROCEDURES.......... 25

13. PSYCHOLOGICAL SAFETY AND MENTAL WELL BEING OF PATIENTS………………................. 28

Outcomes

14. MEASURES ………………………………………………………………………………..................................... 32

15. REFERENCES ……………………....................………………………………………………......................... 34

16. APPENDIX- MEDICATIONS................................................................................................ 43

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INTRODUCTION

On the basis of reports and questions forwarded to the Clinical Risk Managers of the Italian
Network for Health Safety (INSH) from physicians working on the front line, a series of
recommendations have been developed referring to documents and papers published by
national institutions (ISS) and Italian and international scientific societies and journals.

We have arranged the process to describe organising the work system according to the SEIPS
Human Factors approach (1).

1. Assess the work system:

a. Team and organisational culture and communication
b. Environment
c. Tasks required and skills to complete tasks
d. Equipment for patient care and to protect staff
e. The people needed to provide care
f. The patients who will receive care

2. Develop reliable pathways of care.

3. Measure the outcomes of care.

ISQua is honoured to publish these recommendations with our partners in Italy.

The document is work in progress and will be subject to updates by all professionals on a
continuing basis. We appreciate and welcome the contribution of all those involved in COVID-
19, both providers of care and patients who have received care

(e-mail info@insafetyhealthcare.it)

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1. GENERAL RECOMMENDATIONS FOR THE WORK SYSTEM

Building the Team including communication and team culture

1. Emergency task-force should be promptly activated with a clear chain of command, roles
and responsibilities, reliable information sharing tools and proactive approach.

2. Check frequently every day the communications sent by your institutions. Read carefully
and respect them. Alternatively, print and make such communication available in the
ward and share such information during handovers.

3. Clinical risk management units can support dissemination of documents, guidelines issued
by the national institutions for supporting the emergency management, relatively for
measures of prevention to be taken.
Knowledge about Coronavirus transmission and spreading and clinical characteristics of
related disease (COVID-19) are constantly evolving, so that indications for clinical practice
change frequently, i.e. case or suspicion definition, criteria for making tampons, etc.

4. The clinical risk management units must keep contact with front line workers and provide
support. The reporting of adverse events must occur within the task-force activity and be
primarily related to the core activities in time of the pandemic. Secondly, the reporting of
Adverse Events should be encouraged in order to maintain the underpinning safety
climate in order to prompt corrective and improvement actions. Consider quick reporting
tools such as confidential IM or audio-messages (e.g. WhatsApp, WeChat, Telegram, Line
etc.)

5. The clinical risk management units should also receive evidence of good practice so this
can be disseminated.

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Tasks to be undertaken and skills required
1. Organise brief educational training on the correct use of medical and protective devices
targeted to all healthcare workers and develop video tutorials to be available on the
healthcare trust website.

2. Hold refresher courses on hand-hygiene, the prevention of VAP (Ventilator Associated

Pneumonia) and CLABSI (Central Line Associated Bacterial Infection), bundles and the
SEPSIS bundle for early sepsis recognition and management to all healthcare workers (2),
but in particular to the staff not in the frontline of the emergency who could be called as
replacements.

3. Organise early support of expert doctors/nurses with young or colleagues from other
specialties who may be called upon to replace them to properly educate them

4. Do not forget appropriate instructions for environment disinfection (detergents, contact

time, frequency) to cleaners (3).

Equipment needed to protect staff

1. Contact and droplet precautions can be used in routine patient care of patients with
suspected or confirmed COVID-19 (4).

2. Contact and airborne precautions are recommended when performing aerosol generating
procedures (AGPS), including intubation and bronchoscopy (4).

3. Prevent biosafety precautions shortage by extended use and limited re-use of full-face
shields and disposable facial filtering masks (5), by identifying a priority order to the
different wards and by supply of reusable tyvek suits. Store such devices in a locked or
secured area and distribute to staff appropriately (5).
The infection spreads so quickly that a depletion of reserve medical supplies is mandatory.

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Equipment needed to treat patients

1. Give suspected or confirmed patients a surgical mask to put on, at their first contact with
healthcare services (6).

2. In the dedicated care areas for patients with COVID-19, ensure that:
a. haemo-gas analyzers
b. pulse oximeters
c. oxygen therapy
d. ventilator therapy equipment

are available and well-functioning (7).

Environment
1. Strictly apply, without exceptions, the indications for disinfection of environments and
tools (sodium hypochlorite at 0.5% or 70% ethyl alcohol solution) (8).
It is not yet well known how long the virus resists in the environment, but it is inactivated
by solutions based on hypochlorite and alcohol.

2. Prevent germicide deficiency by using galenic preparations.

3. Keep in mind that the creation of dedicated hospitals may divert from the emergencies
/emergencies network. Evaluate carefully the fallout of the timing of treatment decisions
for time-dependent diseases. Consider the use of underused or quiescent equipped
hospitals to meet this need.

4. Unless activity is suspended, in the outpatient (public or private) clinics:

a. avoid gatherings in waiting rooms (recommend people wait outside, respecting the
distance of at least 1m between seats);
b. inform symptomatic subjects with fever and / or cough and / or dyspnea not to go to
clinics;
c. disseminate hygiene and health standards recommendations in the waiting room.

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Patients

1. Reduce hospital admissions, routine outpatient clinic appointments and routine surgical
procedures and regulate hospital visits.

Even in absence of strong evidence, it would be a good practice for authorized family
members to enter the wards wearing medical masks, due to patients’ frailty.

In the full-blown epidemic phase:

a. consider all patients with flu-like symptoms who access hospitals as potentially
affected until proven otherwise (2 negative swabs at least 48-72h apart);
b. create separate unclean/clean paths, even with the help of external mobile
structures (curtains).

2. Contacts of positive patients must follow the instructions provided by those who carry
out epidemiological investigation and be clinically evaluated in the locally designated
sites, only if symptomatic.

3. Use a screening interview to identify suspected cases before admission to the

examination room in case of infection symptoms or to healthcare services for other
reasons (i.e. surgery, coronary angioplasty, labour and delivery, etc.)
a. If the criteria of case or suspicion are met, refer the patient for evaluation,
according to local procedures.
b. General practitioners will provide their patients with useful information by social
networks, email or other tools and keep them updated.

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2. RECOMMENDATIONS FOR DIAGNOSIS

1. The adequate specimen for Real Time-Polymerase Chain Reaction (RT-PCR) testing is
nasopharyngeal and oropharyngeal sampling. Prefer lower respiratory tract (LRT;
expectorated sputum, endotracheal aspirate, or bronchoalveolar lavage) when readily
available (for example, in mechanically ventilated patients). Quality of RT-PCR testing is a
crucial issue. Both pre-analytical and analytical variables should be carefully considered,
and a validation process should be performed according to ISO 15189 (3 protocols). (9)

2. Many of the most common symptoms of novel coronavirus disease (COVID-19) are similar
to those of common flu or cold. So, it is also suggested knowing which common symptoms
of flu or cold are not symptoms of COVID-19. COVID-19 infection seems to rarely cause a
runny nose.
Rhinorrhea ("runny nose") is not a symptom of COVID-19 and nasal congestion ("stuffy
nose) is reported only by 4.8% of patients (10).

3. The most common COVID-19 symptoms are: fever (88%), dry-cough (68%), fatigue (38%),
thick sputum production (34%), shortness of breath (19%), arthromyalgia (15%), sore
throat (14%), headache (13.6%), chills (11%), nausea/vomiting (5%), nasal congestion
(4.8%), diarrhea (3.7%).
Data from a series of 55,924 laboratory confirmed cases of COVID-19 in China in the period
up to February 2020 (11).

4. Beware of patients with gastrointestinal symptoms. Nausea / vomiting and / or diarrhea

can be present in about 9% of cases.
These symptoms have so far been one of the most frequent causes of omission or
diagnostic delays (11).

5. Vital signs measurements (do not forget respiratory rate, please) and blood gas analysis
in ambient air, if SpO2 <94%, at triage or as soon as possible, are essential to correctly
assess patients coming to the emergency room (12, 13).

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6. Do not rely only on PO2 <60 for the diagnosis of respiratory failure, always calculate the
P / F, especially in young subjects.

7. Define a “COVID-19 profile” for the rapid order entry of blood tests, including the
following tests: blood count, C-RP, creatinine, blood glucose, albumin, AST ALT, bilirubin,
pneumococcal and legionella urinary agents, PT-INR, troponin and procalcitonin.

8. Chest X-rays have limited sensitivity in early stages of COVID-19 pneumonia. CT scan is
more sensitive, but raises logistical problems. If ultrasounds competencies are available,
use chest US, but disinfect US probes after contact with every COVID-19 suspected patient
(14).

9. Monolateral lung infiltrates do not exclude COVID-19. They have been described in 25%
of cases (14).

10. The most common reported laboratory abnormalities in COVID-19 patients are:
Lymphopenia (35-75%), increased C-RP (75-93%), LDH (27-92%), ESR (up to 85% of cases),
hypoalbuminemia (50-98%) and anemia (41-50%).
Data from a systematic revision of literature (15).

11. The following negative prognostic factors have been reported: leukocytosis, neutrophilia,
increased procalcitonin, LDH, AST, ALT, total bilirubin, creatinine, troponin, d-dimer, PT
and hypoalbuminemia, lymphopenia. Even thrombocytopenia is associated with severe
disease (15, 16).
Severe lymphopenia and lymphocytes count fall during the first 4 days since hospital admissions
have been associated with a higher mortality. Increased white blood cell count, neutrophil count
and procalcitonin could reflect bacterial superinfection, while increased d-dimer and PT a diffuse
intravascular coagulation (DIC), reported in up to 75% of patients who died (15).

12. History of smoking, respiratory failure, maximum body temperature on admission

≥37.3°C, albuminemia<4 mg/dl would be risk factors for disease progression (severe or

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 critical disease/death).
Results from a multivariate analysis on a small sample (OR ranging from 7 to 15) (17).

13. Do not forget other respiratory infections (legionella, pneumococcus, mycoplasma,

chlamydia, other respiratory viruses) even if during epidemics, so look for other
pathogens and consider antibiotics. During epidemics it is important to avoid availability
bias that means diagnose all infections due to epidemic agents. WHO recommends
investigating other pathogens, as co-infections have been reported (2).

14. Use disease severity stratification for the choice of the treatment setting (home, ordinary,
sub-intensive or intensive care unit).
WHO distinguishes 6 clinical syndromes associated with COVID-19: uncomplicated disease, mild
pneumonia, severe pneumonia, ARDS, sepsis and septic shock. Patients with uncomplicated upper
respiratory tract viral infection, may have non-specific symptoms such as fever, cough, sore throat,
nasal congestion, malaise, headache, muscle pain or malaise. These patients do not have any signs
of dehydration, sepsis or shortness of breath and can be treated at home (2).

15. Pay attention to elderly people and immunocompromised subjects as they can present
vague and/or atypical symptoms (2).

16. Immediately notify the Public Health Officials of COVID-19 positive patients (use infectious
disease notification forms) (18).

17. Criteria for Intensive Care access should be collectively discussed and defined for each
patient in advance involving the medical team and patient/family members, just as any
decision to limit treatment should be collegial, motivated, shared with patient/family
members and documented in medical records. The factors to be considered in such a
decision are: age, functional status, comorbidity, advanced treatment provisions already
expressed, availability of resources and eventual discussion with colleagues with proven
experience.
COVID-19 can lead to a significant increase in the need for ICU beds and a tricky imbalance

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between need and availability, so uncomfortable ethical issues can arise. Clear criteria and early
assessment are essential to avoid hasty and inappropriate decisions (19).

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3. RECOMMENDATIONS FOR HOSPITAL TREATMENT

1. Before prescribing antiviral drugs, verify drug-drug and drug-disease interactions, pay
particular attention to oral anticoagulants that could be substituted by low molecular
weight heparin.
Current antiviral therapy schemes include drugs such as lopinavir / ritonavir, chloroquine or
hydroxychloroquine, darunavir, cobicistat, tocilizumab, remdesivir (13,20) which present
interactions with antibiotics, antiarrhythmics, statins, anti-angina, etc. (Table 1, 2, 3, 4).

2. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers

(ARBs) are safe and should not be discontinued during Coronavirus epidemics (21).

3. There is no proof that ibuprofen can aggravate COVID-19 clinical picture and the European
Medicines Agency is monitoring this issue (22).

4. Start oxygen therapy at 5 L/min and titrate flow rates to reach SpO2 ≥90% in non-pregnant
adults and SpO2 ≥92-95 % in pregnant patients (2).

5. High-flow nasal oxygen (HFNO) or non-invasive ventilation (NIV) should only be used in
selected patients with hypoxemia, respiratory failure (P/F next to 300 for HFNO and 250-
300 for NIV), but with alerts and with preserved ventilator dynamics. Monitor closely for
clinical deterioration (7, 23).

6. Do not prolong HFNO or NIV for over 2 hours in the case of failure to improve (HFNO:
respiratory rate ≥24/min, NIV: respiratory rate ≥28/min and/or worsening P/F for both)
(7, 23).
High flow nasal cannulas and non-invasive ventilation are not recommended in viral pandemics,
based on studies conducted in influenza and MERS (2).

7. Avoid nebulisation therapies for the potential spread of bacteria.

Nebulisers generate aerosol particles that can carry bacteria and viruses deep into the lung. The
risk of infection transmission may increase with nebulisers as they can generate a high volume of

12
 respiratory aerosols that may be propelled over a longer distance than in natural dispersion
pattern. Nevertheless, the larger particles may cause cough in both patients' and bystanders' and
increase the risk of spreading the disease. Nebulisers in patients with pandemic COVID-19
infection have the potential to transmit potentially viable COVID-19 to susceptible bystander hosts
(24).

8. Administer intravenous fluids only if needed and avoid steroids, unless for other
indications.
Excessive fluid administration could aggravate oxygenation and be dangerous, especially in
settings where mechanical ventilation is not readily available. Steroids were not associated with
benefits, but rather with damage in the 2003 SARS epidemic and a delay in virus clearance in
Middle-Eastern Respiratory Syndrome (MERS) of 2012 (2).

9. Assess thromboembolism and bleeding risk of every patient and provide appropriate
thromboprophylaxis.
Consider that recovery times and therefore hypo mobility of a subject with COVID-19 are long (at
least 15 days in mild forms and up to 6 weeks in severe / critical ones) and diffuse intravascular
coagulation (DIC) can complicate the course (2,15).

10. The Respiratory rate, peripheral oxygen saturation (SpO2) and arterial blood gas analysis
results must be monitored closely during hospital stay due to insidious presentation of
severe hypoxemia in this disease. Intra-arterial radial catheters insertion is to be
considered to reduce arterial punctures, even outside ICU.

11. Also monitor white blood cells, lymphocytes and platelets count, LDH, procalcitonin and
d-dimer are considered alarm flags (13, 15, 17).

12. Be aware of an eventual development of severe form +/- 7 days after symptom onset (13).

13. If a patient reports a SpO2 ≤90% in free air or ≤92% in COT and /or presents ≥30 acts/min
and/or severe respiratory distress, intensive care therapist consultation must be required
(25).

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14. Use biosafety precautions when handling oxygen therapy devices (23); cover the patient's
face with a surgical mask during HFNO or C-PAP (23); to reduce the risk of aerosolization,
a. possibly use a dual or single circuit non-invasive ventilator with an integrated
expiratory valve and the helmet as interface (7).

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4. THE ETHICS OF TREATMENT DECISIONS

This is a complex issue which will be decided upon in the local setting as per previous ethical
frameworks.

We recommend that the ethical decision-making process be developed in anticipation of

making complex decisions, rather than in reaction to the need to decide.

With regard to management of the patient affected by COVID-19 in intensive care, we offer a
number of references which will assist in developing the local ethical guidelines. (19, 25, 26,
27).

Other important publications (not included among references):

These provide recommendations that can assist in developing local, though may be context
specific.

Giacomo Grasselli, Antonio Pesenti, Maurizio Cecconi. Critical Care Utilization for the COVID-
19 Outbreak in Lombardy, Italy Early Experience and Forecast During an Emergency Response.
JAMA published online March 2020
https://jamanetwork.com/journals/jama/fullarticle/2763188

Robert D. Truog, Christine Mitchell and George Q. Daley, Robert D. Truog., Christine
Mitchell, George Q. Daley.. The Toughest Triage — Allocating Ventilators in a Pandemic This
article was published on March 23, 2020, at NEJM.org.
https://www.nejm.org/doi/pdf/10.1056/NEJMp2005689?listPDF=true

Ethical Framework for Health Care Institutions Responding to Novel Coronavirus SARS-CoV-
2 (COVID-19) Guidelines for Institutional Ethics Services Responding to COVID-19 Managing
Uncertainty, Safeguarding Communities, Guiding Practice
Hastings Institute
https://www.thehastingscenter.org/wpcontent/uploads/HastingsCenterCovidFramework20
20.pdf

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5. RECOMMENDATIONS FOR SURGERY

These recommendations apply to the medical staff of the operating blocks in case COVID-19.
Patients with COVID-19 may need to undergo emergency and/or emergency surgery. The
following recommendations should be observed (28,29,30):

COVID-19 patient positive asymptomatic

1. Surgical team wearing disposable masks, caps and gloves correctly. Anesthesiologist and
assistant nurse: DPI FFP2.
2. Patients must wear a medical mask until I.O.T. (oro-tracheal intubation).
3. Airway protection of the patient also intubated with TNT drapes compatible with
anesthesiologist assistance.

Symptomatic or having few or minor symptoms positive COVID-19 patient

1. Surgical team wears FFP2 or FFP3 and PPE masks.

2. Anesthesiologist and nurses assigned to direct assistance: FFP2 / FFP3 masks and PPE.
3. Patients must wear a medical mask for the entire time of surgery and / or after the IOT
procedure for airway protection with compatible TNT drapes.

Patient COVID-19 sick and in invasive airway management.

1. All professionals must wear PPE and FFP2 / FFP3.

While staying in the operating room it is recommended to utilise laminar flow according to
current legislation and post-intervention sanitisation for at least 1 hour.

Team working and organisation

Surgical teams in order to stay healthy and maintain continuity of care should divide into
teams of senior and junior doctors and work for a 2 week period. After the 2 weeks, teams
will come in to release the other. This will allow easier replacement of team members should
they fall ill and potential containment of the virus to smaller staff numbers and an ability to
maintain some service provision and clinical care.

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6. RECOMMENDATIONS FOR PREGNANT WOMEN

1. Reduce access of pregnant women to prenatal care, limiting only to high-risk cases (31).
There is no evidence of an increased risk of unfavourable maternal or foetal outcomes in the case
of COVID-19. However, evidence relating to influenza and SARS-COV1 must induce to consider the
pregnant woman as a high-risk patient.

2. Infants born to mothers with confirmed COVID-19 should be considered as suspects. As

such, these infants should be isolated from others (32).

3. Separation (i.e. in an individual room) of the infant from the mother with COVID-19
confirmed or suspected, until the precautions based on the transmission risk of the mother
are suspended. The decision should be discussed carefully between the caring team and
the mother, evaluating risk and benefits of this choice, including the protective potential
of colostrum, breast milk and feeding time. (31,32).

4. The discharge of mothers after childbirth must follow the recommendations for discharge
of COVID-19 or suspected patients (31).

5. In the case of a woman with suspected SARS-CoV-2 infection or with COVID-19, according
to her clinical conditions and desire, breastfeeding should be started and / or maintained
directly on the breast or with squeezed breast milk (25). If mother and child must be
temporarily separated because of mother clinical conditions, one should help the mother
to maintain milk production through manual or mechanical/electric squeezing (32).
In a limited series reported to date, the presence of the virus in the breast milk of infected women
has not been reported, but anti-SARS-cov2 antibodies have been found (30). So breast milk would
be protective.

6. A mother with confirmed COVID-19 or ongoing swab samples because symptomatic should
take all possible precautions to avoid spreading the virus to the baby, including washing
hands before touching the baby and wearing a face mask, if possible. during breastfeeding.
If using a manual or electric breast pump, the mother must wash her hands before

17
 touching the breast pump or parts of the bottle. If possible, have another person
administer the milk to the baby (32).

It is not yet known whether COVID-19 can be transmitted through breast milk. At present, the main
concern is not whether the virus can be transmitted through breast milk, but rather whether an
infected mother can transmit the virus through respiratory droplets during breastfeeding (31).

7. For assisting the delivery of women with confirmed or suspected COVID-19, staff must use
the safety precautions provided for non-pregnant patients (32).

8. Pregnant women with suspected or confirmed SARS-COV2 infection should be treated with
supportive therapies, however taking into account the physiological characteristics of
pregnancy (2).

9. The use of experimental therapeutic agents outside of a research study should be guided
by an individual risk-benefit analysis based on the potential benefit to the mother and the
safety of the foetus, with the consultation of an obstetrician specialist and an ethics
committee (2).

10. The decision to proceed to a pre-term birth is based on many factors: gestational age,
maternal conditions and foetal stability and requires a collegial evaluation by obstetric,
neonatal and intensive care specialists (depending on the mother's condition) (2).

11. Positivity in itself to Coronavirus is not an indication for a caesarean section which in these
patients should only be performed based on other obstetric or medical indications (32).

12. In COVID-19 pregnant women, it is useful to be very cautious in inducing maturity of the
lung by means of corticosteroids, since these drugs seem to worsen the course of the
infection. If possible, evaluate each case with a neonatologist.

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7. RECOMMENDATIONS FOR PEDIATRIC PATIENTS

Keep in mind that:

1. To date there is a paucity of information regarding COVID-19 in children.

2. Children and infants are affected and with milder forms (X-ray more often negative; CT
more sensitive) (33, 34).

3. A small series of children with COVID-19 has shown a greater prevalence of peripheral
halo (halo-sign) lung consolidations on CT.

4. The criteria for the definition of Acute Respiratory Distress Syndrome (ARDS) and septic
shock, the guidelines for the management of sepsis and septic shock and the use of non-
invasive ventilation in children are different from those of adults (2).

5. Children desaturate more easily during intubation; therefore, it is important to pre-

oxygenate with 100% O2 with a mask with a reservoir before intubating (2).

6. A rectal swab may be useful in children to determine the timing of the termination of
quarantine.

Some authors have used the cycle threshold values of the serial rectal and nasopharyngeal swab
tests to indicate viral load. Interestingly, the measurements have indicated that viral shedding
from the gastrointestinal system could be greater and last longer than the respiratory tract (35,
36).

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8. RECOMMENDATIONS FOR HOSPITAL DISCHARGE

1. The patient with fever without respiratory failure (normal EGA and walking test) and
normal chest x-ray, <70 years and without risk factors (lung disease, diabetes mellitus and
/ or heart disease) can be discharged from the emergency room (13, 20) with indication
of home isolation, waiting to run the swab sampling or its result.

The discharge physician:

 obtains a telephone number to contact the patient for swab sampling and / or to
communicate the result;
 provides information on how to access the pad (where and when).

If the swab test does not take place in the emergency department, but is performed
elsewhere to another area or hospital, it is strictly suggested to use systems to avoid the
loss of information.

The facility / service running the buffer

 must report the result as soon as it is available to the patient and, if positive, to the
Public Health Department for establishing active surveillance.

2. At the end of the hospitalisation, write clearly on the discharge letter:

 CLINICALLY CURED patient (patient with clinical symptoms resolution, but still positive
for swab) (37)
or
 CURED patient (patient who, in addition to resolving the symptoms, is negative in two
consecutive swabs, carried out at least 24 hours apart) (37).

or

 CLINICALLY CURED PATIENT: write clearly on the discharge letter the indication to be
observed at the home quarantine until the swab is negative on two determinations
after 24 hours and the execution methods of the control buffer.

20
Although there is no clear supported evidence, it is considered appropriate to suggest patient
retesting no earlier than 7 days and, if negative, confirm the negativity after at least 24 hours (37).

or

DISABLED PATIENT, roommate of patient with positive swab or whose result is not yet
known:
 Write clearly the indication of home isolation on the discharge letter (up to 14 days
from contact with the infected person) and indication to call the appropriate number
( in Italy 112) if symptoms appear;
 Assure a telephone number to communicate buffer result;
 Communicate swab results as soon as available to the patient and, if positive, to public
health trusts, in order to establish active surveillance (37).

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9. RECOMMENDATION FOR HOME ISOLATION

1. Provide prevention measures and explain them to patients in home isolation also by
using designs, charts or pictures.

2. Give also clear indications on alarm symptoms:

a. promote information

b. diffusion of telephone numbers to call in case of occurrence of symptoms

c. Arrangements for support e.g. shopping

3. Provide call centers, online chats, FAQs and video tutorials to consult when there
is doubt.

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10. RECOMMENDATIONS FOR PERSONS IN QUARANTINE (38)

1. Information represents the key success factor; quarantined persons must be

constantly informed and updated on the epidemic progress.

2. It is necessary to provide food and other materials and any necessary drugs without
making people feel abandoned or alone.

3. The quarantine period should be short, and the duration should not be modified
except in extreme circumstances.

4. Most of the side effects derive from the freedom restriction imposition; voluntary
quarantine is associated with less stress and fewer long-term complications;
therefore, it is necessary to explain clearly the reasons for such suggested behaviours.

5. Public health officials should stress the selfless choice of self-isolation.

Quarantined healthcare workers can be helpful in producing useful documents or

other materials while at home for their colleagues. They could contribute by making
suggestions and stay in touch with social media.

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11. RECOMMENDATIONS FOR ONCOLOGIC AND IMMUNOSUPPRESSED PATIENTS

1. Do not indiscriminately discontinue antineoplastic or immunosuppressive therapies.

(39-41).

2. In cancer patients, consider the possibility of postponing the treatment cycle on a

case-by-case basis (39).

3. Immunosuppressant withdrawal is indicated if symptoms suggestive of infection

appear (40); in this case it is good practice to inform the physician responsible for the
treatment promptly.

4. Steroids can be continued, but with caution (40).

5. New immunosuppressant prescriptions or dose increases are not recommended

during an epidemic (41).

6. Consider the switch from parenteral drugs to others that can be administered at home
(e.g. subcutaneously) to reduce access to outpatient clinics (40).

7. Ensure non-deferred outpatient visits and postpone visits for long-term follow-up,
after remote evaluation (telephone, email, etc.) (39, 40).

8. Do not allow visitors in therapy rooms and allow the presence of a maximum of one
visitor per patient in hospital stays (38).

Please refer also to General Recommendations (section 1) for other indications relating to
outpatient clinics.

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12. MORTUARY/MORGUE OPERATING PROCEDURES

Management of the deceased body with suspect, probable or confirmed COVID-19

respiratory infection

The proposed procedure is aimed at the safe management of the phases of acceptance,
handling, custody, and discharge of the body with suspected, probable or confirmed diagnosis
of COVID-19 (42). The objective has been pursued by drawing up the following
recommendations:

1. The acceptance and handling of the body must be done by personnel equipped wearing
the recommended PPE;
2. The body must be positioned on a sanitised metal stretcher for custody and subsequent
investigations.
3. At the end of the investigations, the body must be placed in the coffin with the clothes
and wrapped in a sheet soaked in disinfectant solution.
4. If the corpse is required to remain in the mortuary is necessary, pending or at the
conclusion of the investigations, the same must take place inside a special closed body
bag and dedicated refrigerated room.
5. At the end of the handling and transport operations, all the equipment used must be
subjected to sanitisation.

Recommendations for autopsy investigation in cases of suspect, probable or confirmed

COVID-19.

For the safe and effective performance of HG3 (Hazard Group 3) autopsy investigations, is
required:
 generic risk assessment and adoption of universal standard precautions;
 knowledge of possible pathological findings that can be highlighted;
 the definition of SOP (Standard Operating Procedures) for the management of autopsies
with high biological risk.

25
1. The use of universal precautions effectively protects against most risks related to SARS-
CoV-2 infection. Professionals have a duty to carry out risk assessment for each case in
order to prevent actions that could put operators at risk (43).

2. At the end of the autopsy investigations, the body must be positioned in a body bag and
transported in a refrigerated room.

3. Disinfect the outside of the body bag with a hospital disinfectant applied according to the
manufacturer's recommendations. It is also recommended in this phase the use of
suitable PPE by each operator involved in the movement and exit phases of the body.

Disinfection of autopsy rooms

In addition, following an autopsy on a subject with suspect or confirmed COVID-19, the
following recommendations for disinfection of autopsy rooms should be applied (44):
1. keep ventilation systems active during cleaning;
2. wear disposable gloves when cleaning and handling cleaning or disinfectant solutions;
3. dispose of gloves after cleaning; do not wash or reuse the gloves in any case;
4. use eye protection, such as a visor or goggles, if splashing is expected;
5. if necessary, use respiratory protection based on the type of detergent or disinfectant;
6. wear a long-sleeved waterproof device to protect skin and clothing;
7. use disinfectants with indications of efficacy against human coronaviruses;
8. clean the surfaces and apply the disinfectant ensuring an adequate contact time for
effective disinfection;
9. comply with the safety precautions and warnings indicated on the product label (for
example, allow adequate ventilation in restricted areas and ensure correct disposal of the
unused product or used containers);
10. avoid product application methods that cause the production of splashes or aerosols.

Regarding environmental disinfection, the available evidence has shown that coronaviruses
are effectively inactivated by adequate sanitisation procedures that include the use of
common hospital disinfectants, such as sodium hypochlorite (0.1% -0.5%), ethanol (62- 71%)
or hydrogen peroxide (0.5%). There is currently no evidence to support a greater

26
environmental survival or a lower sensitivity of SARS-CoV-2 to the aforementioned
disinfectants.

1. Hard and non-porous surfaces can be cleaned and disinfected as previously described.

2. Handle with gloves and disinfect properly after use, equipment such as cameras,
telephones and keyboards, as well as all objects that remain in the autopsy room.

3. Cleaning activities must be supervised and periodically checked to ensure that correct
procedures are followed. Sanitation personnel must be properly trained and equipped
with suitable PPE.

4. After cleaning and removing the PPE, wash the hands immediately. Avoid touching the
face with gloved or unwashed hands.

5. Environmental disinfection must include cleaning with water and detergent soap on all
vertical and horizontal surfaces, followed by disinfection with hospital disinfectants
effective against SARS-CoV-2.

6. For environmental decontamination, it is necessary to use dedicated or disposable

equipment. Reusable equipment must be decontaminated after use with a chlorine-based
disinfectant. The use of special trolleys is strongly recommended, different from those
used for cleaning common areas.

7. The instruments used for autopsies should be autoclaved or treated through chemical
sterilisers.

27
13. PSYCHOLOGICAL SAFETY OF STAFF AND MENTAL WELLBEING OF PATIENTS

Psychological safety of staff (45, 46, 47, 48)

1. Create a healthy work, ethos and environment during crises and also to have systems in
place to deal with subsequent distress and disorder.

2. Organisations which have the foresight to prepare their staff to deal with trauma might
consider using interventions such as PFA (Psychological First Aid is a humane, supportive
response to a fellow human being who is suffering and who may need support).

3. Consider that factors negatively affecting the psychological well-being of staff are:
 concerns over the contracting the illness
 concerns for safety of their family
 witnessing the death of colleagues
 isolation from family and colleagues
 sense of being underappreciated
 extended length of epidemic

4. Reduce mental health stigma to be reduced. The best ways of reducing stigma were
believed to be raising awareness of mental health issues and telling people that it’s quite
normal to feel that way and have those feelings;

5. Educate healthcare workers who are exposed to trauma about the effects of cumulative
stress. The training should be delivered either online ‘because they can do it at their own
convenience’ or via educational leaflets ‘rather than finding the time to spend on a day
course’
The education about psychological trauma may lead to better understanding, better recognition
of symptoms in oneself and in others, less judgement, and therefore reduced stigma, and that
positive relationships with others in the workplace can have a positive impact on psychology.

28
6. Maintain teamwork and effective leadership while at the same time providing individuals
the opportunity to provide input into the decisions that affect their lives.
Staff often experience severe emotional stress during viral outbreaks. It is often the nursing staff
who feels the greatest level of stress due to their constant contact with sick patients, who may
not be improving despite the nursing staff's best efforts. Physicians usually cope somewhat better
with this situation because they are in a position to make treatment decisions and are less directly
involved in implementing patient care.

7. Be receptive to suggestions from nursing staff and support personnel.

Input is empowerment and provides a sense that these critical staff retain some control over their
situation. If suggestions are not acted on, clear explanations as to why they were not should be
provided and alternatives should be explored.

8. Administration needs to be supportive of staff and not be seen as pedantic and overly
controlling.
In cases where staff and support personnel did not feel appreciated or listened to, there was a
high degree of dissatisfaction and an increased occurrence of absenteeism and staff strikes, which
further reduced personnel in an already-strained system.

9. Take care of yourself and your loved ones. Healthcare providers are not invulnerable to
experiencing their own emotional distress during outbreaks, and this distress can be
compounded by caring for sick and distressed patients.

10. Make sure your basic needs are met, including: eating, drinking, and sleeping; take a break
when you need one; check in with loved ones; practice the strategies to reduce distress
listed above; and monitor yourself for stress reactions too.

11. Make efforts to ensure that your office and/or organisation has a viable plan to monitor
the course of the outbreak and take rapid and appropriate action if needed.

29
Mental well-being of Patients (49)

1. Medical and mental health clinicians are likely to encounter patients who are experiencing
various levels of emotional distress about the outbreak and its impact on them, their
families, and their communities.
We must consider that COVID-19 patients have long hospital stays and in the early stages they will
experience the anguish of having an aggravation of the disease with the possibility of being
intubated. Furthermore, the limited staff available will not be able to guarantee them continuous
assistance and their relatives as well.

2. Providers should acknowledge uncertainty about emerging diseases and help patients
understand that there is often an emotional component to potential health concerns.

3. Providers should be cognisant that the symptoms might extend beyond classical mental
health symptoms to include relational struggles, somatic, academic, or vocational issues.

4. Every person, including mental health providers, can either react in fear, anger, or despair
and regress, or can choose resilience and play as an active part of the solution.

In addition, providers should consider the following recommendations for promoting

patients’ mental wellbeing during emerging infectious disease outbreaks:

Be informed: Obtain the latest information about the outbreak from credible public health
resources in order to provide accurate information to your patients.

Educate: Healthcare providers are on the front lines of medical intervention and in a position
to influence patient behaviors for protecting individual, family, and public health.
Psycho-education is of utmost importance in the aftermath of disasters. Patient education plays a
critical role in both containing the disease and mitigating emotional distress during outbreaks.
Depending on the nature of the outbreak, this can range from education about basic hygiene such as
hand-washing and cough etiquette to more complex medical recommendations for prevention,
diagnosis, and treatment.

30
5. Let patients know what you, your office, or your organisation is doing to reduce the risk
of exposure.

6. Correct misinformation.
In this age of social media, misinformation can spread quickly and easily, causing unnecessary
alarm. If patients present you with inaccurate information related to the outbreak, correct their
misconceptions and direct them to vetted public health resources.

7. Limit media exposure.

The excess media exposure to coverage of stressful events can result in negative mental health
outcomes. Use trusted media outlets to gather the information you need, then turn them off—
and advise your patients to do the same.

8. Anticipate and counsel about stress reactions.

Emotional distress is a common mental condition in the context of uncertain and potentially life-
threatening situations, such as COVID-19 epidemic. A good first step for mitigating your patients’
stress is to acknowledge that it exists and help normalise it (“I see that you’re stressed, and that’s
understandable. Many people are feeling this way right now.”).

9. Teach patients to recognise the signs of distress, including worry, fear, insomnia, difficulty
concentrating, interpersonal problems, avoiding certain situations at work or in daily
living, unexplained physical symptoms, and increased use of alcohol or tobacco.
This will help them become more aware of the state of their mental health and head off distress
before it becomes harder to manage.

10. Discuss strategies to reduce distress, which can include:

 Being prepared (developing a personal/ family preparedness plan for the outbreak).
 Taking everyday preventive measures (e.g., frequent handwashing).
 Maintaining a healthy diet and exercise regimen.
 Talking to loved ones about worries and concerns.
 Engaging in hobbies and activities you enjoy to improve your mood.
 If a patient is experiencing severe emotional distress or has a diagnosable mental
illness, refer for specialized mental health care.

31
14. MEASURES (50,51,52)

It is important that we measure the impact of our actions. We include some measures that
may be of use.

Outcome measures

Outcome measures should be collected in order to support the monitoring of effective

provider (hospital) epidemic/pandemic response including the capacity to adequately treat
patients with other common severe conditions like heart attacks, strokes, trauma, COPD in
order to assure that the health of the public is protected to the fullest extent possible:

1. Hospitalisation rate for COVID-19 (indirect outcome measure of the territory).

2. In-hospital Mortality rate of patients hospitalized for COVID-19.
3. Average Length of Stay of COVID-19 patients.
4. Percentage of COVID-19 patients admitted to ICU.
5. In-hospital mortality rate of NO-COVID-19 patients hospitalised for AMI.
6. In-hospital mortality rate of NO-COVID-19 patients hospitalized for Stroke.
7. In-hospital mortality rate of NO-COVID-19 patients hospitalized for COPD.
8. Percentage of NO-COVID-19 hospitalized patients that acquired COVID during the
hospitalisation.
9. COVID-19 infection rate among staff / Number of tests performed to hospital staff (as
process measure)
10. Survival rates

Where possible indicators 1-7 should be stratified by age groups.

Additionally, the proposed outcome measures should be used and interpreted with great
caution if used to benchmarking care quality between providers. In this case, consistent data
definitions should be adopted and measures from 1 to 7 should be adjusted for potential
confounding factors (i.e. patient case mix) in order to draw meaningful and correct
comparisons among providers of Mortality rate

32
Length of stay measures
1. Length of Stay
2. Average length of stay in ICU of infected
3. Average length of stay in hospital

Process Measures (some examples)

1. Percentage of infected individuals admitted to ICU
2. Percentage of people with comorbidities
3. Percentage of staff with and without correct equipment
4. Number of patients not treated in appropriate level of care
5. Percentage staff trained to use equipment

Balancing measures
1. Staff infection rate
2. Staff mortality rate
3. Staff well being
4. Illness and sickness rates
5. Mental illness

Patient profiles to consider

 Age
 Gender
 Ethnicity
 Comorbidity
 Region
 Contacts

33
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41
15. APPENDIX - MEDICATIONS

TABLE 1 - Chloroquine and hydroxy-chloroquine: main drug interactions

DRUGS INTERACTIONS

Chloroquine Antacids based on aluminum, calcium and magnesium and kaolin can reduce
their absorption

In association with:

 Corticosteroids accentuation of any myopathies or cardiomyopathies

 Phenylbutazone can induce exfoliative dermatitis
 Isoniazid, Amiodarone, Carbamazepine, Phenytoin, Phenothiazide,
Ketoconazole and MAO inhibitors (Mono-Amino-Oxidase Inhibitors)risk
of hepatotoxicity
 Mefloquine and bupropion risk of convulsions
 Metronidazole possible dystonic reactions
 Penicillamine serious haematological or renal adverse events
 Pyrimetamine / sulfadoxineskin reactions

Effects of chloroquine on other drugs:

 Ampicillin reduced absorption (administer at least 2 hours after

chloroquine)
 Class IA and III antiarrhythmics, Tricyclic antidepressants, Antipsychotics
increased risk of ventricular arrhythmia
 Antiepileptic antagonism on anticonvulsant effects
 Cyclosporine increase in plasma concentration
 Digoxin increase in plasma concentration and relative toxicity
 Methotrexate potentiation of the action
 Neostigmine and Pyridostigmine antagonism of the effects
 Vaccines antibody response reduction ONLY with rabies vaccine

42
Hydroxy- In association with:
chloroquine
 Phenylbutazone can induce exfoliative dermatitis
 Isoniazid, Amiodarone, Carbamazepine, Phenytoin, Phenothiazide,
Ketoconazole and MAO inhibitors (Mono-Amino-Oxidase Inhibitors)can
cause hepatoxicity

Effects of hydroxychloroquine on other drugs

 Antiepilepticsantagonism on anticonvulsant effects

 Cyclosporine increased plasma concentrations
 Digoxin increased plasma concentration and relative toxicity
 Insulin and Antidiabetics potentiation of hypoglycemic effects

43
TABLE 2 - LOPINAVIR/RITONAVIR: Main interactions and recommendations

Coadministered Drug Mechanism of interaction Clinical Recommendations

RETROVIRAL AGENTS: Specialist advice, dose

Nucleoside reverse adjustment is not required in
transcriptase inhibitors most cases. Co-
(NRTIs), Non-nucleoside administration with other
reverse transcriptase HIV protease inhibitors (PIs),
inhibitors (NNRTIs), HIV CCR5 according to current
- antagonist, Integrase guidelines, is not
inhibitor, Inhibitors of HIV recommended.
protease

Antacids No contraindications

Alpha antagonists

ALFUZOSIN Increased concentration Contraindicated

(CYP3A inhibition) (hypotension)

Analgesic Drugs

FENTANYL Increased concentration Close monitoring (risk of

(CYP3A inhibition) respiratory

Antianginal Drugs

RANOLAZINE Increased concentration Contraindicated

(CYP3A inhibition)

44
Antiarrhythmics

AMIODARONE, Increased concentration Contraindicated (arrhythmia)

DRONEDARONE (CYP3A inhibition)

DIGOXIN Increased concentration Plasma level monitoring

(P-gp inhibition)

BEPRIDIL, SYSTEMIC Increased concentration Plasma level monitoring

LIDOCAINE, QUINIDINE

Antibiotics

CLARITHROMYCIN Moderate increase of Dose reduction in kidney

under-curve area (CYP3A failure(CrCL<30 ml/min);
inhibition) attention in patients with
impaired liver and kidney
function

Antineoplastics Specialist Advice

Anticoagulants

WARFARIN CYP2C9 induction INR monitoring

RIVAROXABAN AUC: ↑ 153%, Cmax: ↑ Contraindicated (bleeding)

55%

(CYP3A and P-gp

inhibition)

45
VORAPAXAR Increased concentration Contraindicated
(CYP3A inhibition)

Antiepileptic

PHENYTOIN Concentrazioni diminuite Plasma level monitoring

(induzione del CYP2C9 e
del CYP2C19)

CARBAMAZEPINE, Increased Carbamazepine Plasma level monitoring

PHENOBARBITAL concentration (CYP3A
inhibition); reduced
Lopinavir concentration
(CYP3A induction)

Antidepressants and
anxiolytics

TRAZODONE AUC: ↑ 2,4 times Dose reduction

Antifungals

KETOCONAZOLE Increased concentration Dose reduction

(CYP3A inhibition)

Anti-gout

COLCHICINE AUC: ↑ 3-times; Cmax: ↑ Contraindicated

1,8-times (CYP3A and/or
P-gp inhibition)

46
Antihistamines

ASTEMIZOLE, TERFENADINE Increased concentration Contraindicated (severe

(CYP3A inhibition) arrhythmias)

Anti Infectives

Fusidic Acid Increased concentration Contraindicated

(CYP3A inhibition) (rhabdomyolysis)

Antimycobacterial agents Specialist Advice

Benzodiazepines

MIDAZOLAM Oral administration: AUC: Oral administration

↑ 13-times contraindicated; close
monitoring for parenteral
parenteral administration:
administration
AUC: ↑ 4-times (CYP3A
inhibition)

Beta2 agonists

SALMETEROL Increased concentration Contraindicated (severe

(CYP3A inhibition) cardiovascular event and
arrhythmias)

Calcium Channel Blockers

47
FELODIPINE, NIFEDIPINE,
NICARDIPINE

Steroids

DEXAMETHASONE Reduction of Lopinavir Clinical monitoring of anti-

concentrations (CYP3A viral activity
induction)

Phosphodiesterase inhibitors

AVANAFIL, SILDENAFIL Increased concentration Contraindicated

(CYP3A inhibition)

Ergot Alkaloids

DIHYDROERGOTAMINE AND Increased concentration Contraindicated

OTHERS (CYP3A inhibition)

Intestinal Prokinetics

CISAPRIDE Increased concentration Contraindicated

(CYP3A inhibition)

Direct anti-HCV agents Increased plasma Contraindicated

concentration (combined
mechanisms)

HCV protease inhibitors Contraindicated

48
Immunosuppressers

CICLOSPORINE Increased concentration Plasma level monitoring

(CYP3A inhibition)

Statins Contraindicated; fluvastatin

and pravastatin tolerated

Opioids

METHADONE Decrease in concentration Plamsalevelmonitoring

Contraceptives

Ethinylestradiol Decrease in concentration Use additional contraceptive

methods

Hormone Replacement
Therapy (HRT)

Levothyroxine Potential interactions not TSH monitoring

well documented
during the first month from
the beginning and / or from
the end of the treatment

49
TABLE. 3 DARUNAVIR/COBICISTAT: Main interactions and recommendations

Co-administered drug Interaction mechanism Clinical recommendations

Anti-retroviral agents (HIV)

Inhibitors of the strand Specialist advice, no dose

transfer of ' integrase , adjustment necessary, except
inhibitors nucleoside / for Emtricitabine / tenofovir
nucleotide HIV reverse alafenamide
transcriptase inhibitors (NRTIs)

Non- nucleoside / nucleotide Specialist advice, non-

inhibitors of HIV reverse recommended co-
transcriptase (NNRTI) administration RILPIVIRINE,
the increase of which is not
considered relevant, is an
exception

CCR5 A ntagonists No dose adjustment necessary

MAVAVIROC Increased concentration Specialist advice for dose

(CYP3A inhibition) adjustment

Al / M or calcium carbonate No dose adjustment

based antacids

Alpha antagonists

ALFUZOSIN Increased concentration Contraindicated

(CYP3A inhibition) (hypotension)

Anaesthetic

50
AL FENTANYL Increased concentration Dose reduction and
(inhibition of CYP3A4) monitoring (respiratory
depression risk)

Antianginal/tymic antiaries

AMIODARONE, Increased concentration contraindicated

DRONEDARONE CHINIDINA, (inhibition of CYP3A and/or
BEPRIDILE, IVRABRADINA, CYP2D6 )
RANOLAZINA

DYSOPYRAMID, FLECAINIDE, Increased concentration Caution and monitoring

SYSTEMIC LIDOCAINE, (inhibition of CYP3A and/or
MEXILETINE, PROPAPHENONE CYP2D6)

digoxin Increased concentration (P- Dose titration and accurate

glycoprotein inhibition) monitoring of drug
concentration

Antibiotics

Clarithromycin Increased AUC (CYP3A Caution dose adjustment in

inhibition) patients with renal
impairment ( CrCL <30 ml /
min )

Anticoagulants

WARFARIN Theoretical mechanism of INR monitoring

alteration of plasma
concentrations

51
APIXABAN, EDOXABAN, Increased plasma contraindicated
RIVAROXABAN concentrations (inhibition
of CYP3A and P-gp )

DAPIGATRAN; ticagrelor Increased plasma contraindicated

concentrations

(inhibition of CYP3A and P-gp

)

Anticonvulsants

clonazepam Increased concentration Clinical monitoring

(CYP3A inhibition)

CARBAMAZEPINA, Reduced concentrations of Contraindicated

FENOBARBITALE, FENITOINA darunavir and/or cobicistat
(CYP3A induction).

Antidepressants and
anxiolytics

ST. JOHN'S GRASS Reduction of darunavir and / contraindicated

or cobicistat concentrations
(CYP3A induction).

PAROXETINE, SERTR ALINA, Increased plasma Dosage reduction and clinical

AMITRIPTILINA, DESIPRAMINA, concentrations monitoring
IMIPRAMINA, NORTRIPTILINA, (CYP2D6 and/or inhibition

TRAZODONE CYP3A)

Antidiabetic

52
METFORMIN Increased plasma Dosage reduction and clinical
concentration monitoring

Co-administered drug Interaction mechanism Clinical recommendations

antiemetics

DOMPERIDONE Not studied contraindicated

Anti-fungals

CLOTRIMAZOLO, Increased concentration Caution, clinical monitoring

FLUCONAZOLO, (inhibition of CYP3A and /or and dosing
ITRACONAZOLO, P-gp ) Voriconazole contraindicated
ISAVUCONAZOLO,
POSACONAZOLO

Anti-gout

colchicine Increased concentration Dosage reduction,

(inhibition of P- gp and/or contraindicated in the

CYP3A4) presence of hepatic or renal

impairment

H2 receptor antagonists No dose adjustment necessary

Antimycobacterials Specialized evaluation,

tendentially contraindicated

Anti-psychotics / neuroleptics

53
PERFENAZINA, RISPERIDONE, Increased plasma Dose reduction and clinical

TIORIDAZINA concentrations (inhibition of monitoring

CYP3A, CYP2D6
and/or P- gp )

LURASIDONE, PIMOZIDE, Contraindicated

SERTINDOLO, QUETIAPINA

Anti-cancer Theoretical mechanism of Specialist evaluation, extreme

concentration increase caution
(CYP3A inhibition)

Beta2 agonists

SALMETEROL Increased concentration Contraindicated (serious

(CYP3A inhibition) cardiovascular adverse events,
arrhythmias)

Beta blockers

CARVEDILOL, METOPROLOL, Plasma concentrations Dose reduction and clinical

TIMOLOL increased monitoring
(CYP3A inhibition)

Calcium antagonists

AMLODIPINA, DILTIAZEM, Increased concentration Dose reduction and clinical

FELODIPINA, NIFEDIPINA, (inhibition of CYP3A and / or monitoring
NICARDIPINA, VERAPAMIL CYP2D6)

Corticosteroids

54
dexamethasone Reduction of Darunavir and / Caution
or cobicistat concentrations
(CYP3A induction)

Proton pump inhibitors No dose adjustment

Inhibitors of
phosphodiesterase

TADALAFIL, SILDENAFIL Increased concentration Contraindicated

(CYP3A inhibition)

Antivirals direct action against Increased plasma Contraindicated

HCV (inhibitors NS3-4A concentrations (combination
protease) of mechanisms)

Endothelial receptor Increased concentration Contraindicated

antagonists (Bosentan ) (theoretical consideration)

Immunosuppressant

CYCLOSPORINE Increased concentration ( Monitoring of drug levels

CYP3A inhibition)

everolimus contraindicated

Narcotics, Opioids

METHADONE Increased concentration Monitoring of drug levels

(theoretical consideration)

Buprenorphine / naloxone Increased concentration Clinical monitoring

(theoretical consideration)

55
FENTANYL, OXYCODONE, Increased concentration Clinical monitoring
TRAMADOL (theoretical consideration)

Opioid antagonists

NALOXEGOL Not studied contraindicated

Sedatives / hypnotics

BUSPIRONE, CLORAZEPAM, Increased concentration ( Caution, dose reduction and

DIAZEPAM, ESTAZOLAM, CYP3A inhibition) clinical monitoring
FLURAZEPAM, ZOLPIDEM

MIDAZOLAM (PARENTERAL) Only in intensive care.

MIDAZOLAM (ORAL) contraindicated

Urological drugs

FESOTERODINA, Not and clever or Caution, dose reduction and

SOLIFENACINA clinical monitoring

DAPOXETINE Not and clever or contraindicated

Contraceptives

Alteration of plasma Use additional methods of

concentrations contraception

drospirenone Monitoring for possible

hypokalaemia

56
Statins and other hypo- Contraindicated
lipidemic agents (Lomitapide)

57
TABLE 4 Serious adverse effects

Lopinavir / Darunavir / Chloroquine Hydroxychl Tolicizumab

Ritonavir cobicistat oroquine

Serious Hypersensitivit Hepatotoxicity QT Hypoglycemi Interstitial

adverse y reaction, prolongation a pneumonia
effects angioedema Anorexia, & Torsades de Infections
Stevens- Pointes QT
Johnson hyper- prolongation Leukopenia,
syndrome / cholesterolaemia Reduction in neutropenia
Toxic , seizure Cardio- hypo-
epidermal threshold myopathy fibrinogenemia
necrolysis / hyper-
Erythema triglyceridemia Anaphylaxis Muscle Upper respiratory
multiforme or asthenia infections
QT Renal failure anaphylactoid
prolongation & reaction Retinal or Herpes simplex
Torsade de Stevens-Johnson visual field and zoster
Pointes syndrome (rarely Neuromuscul alterations
) ar impairment Oral ulcerations
AV block, PR Skin
prolongation Neuropsychia reactions Complicated
tric disorders diverticulitis
Hyperglycemia, (potential to
hypertriglyceri increase Hepatotoxicity
demia delirium)

Renal failure Pancytopenia,

neutropenia,
Anemia, thrombocyto
leukopenia, penia, aplastic
neutropenia anemia

Pancreatitis Hepatitis

58
 Hepatotoxicity

Commo Nausea / Nausea / Nausea / Nausea / Hypertension

n vomiting, vomiting, vomiting, vomiting, Headache
adverse diarrhea diarrhea diarrhea, diarrhea,
reaction Insomnia, Insomnia, abdominal abdominal Skin reactions
s anxiety anxiety pain pain
Headache Visual Conjunctivitis
Rash Visual disturbance,
Muscle Pain disturbance, headache Hyper-
headache Skin rash, cholesterolemia
itching
Extrapyramid Abdominal pain,
al symptoms Extra- gastritis
pyramidal
symptoms Cough, dyspnea

Contra- Cardiac disease Liver failure Porphyria Porphyria Administration

indicated ischemic heart (class C Child- G6PD Retinopathy of alive or
in: disease, Pugh) deficiency attenuated
cardiomyopath Epilepsy Maculopathi vaccines
y, structural Haemophilia Heart failure es
heart disease, Recent Children <6a
QT myocardial <31 Kg
prolongation infarction

Liver disease

Monitor Transaminases Kidney function Serial Blood Cholesterol,

complete count, blood count,
blood count glycemia, transaminases
QT interval QT interval

59